Human Leukocyte Antigen–Matched Donor Allo-HSCT in ALL as First Remission Therapy

Although a large body of clinical data exists using myeloablative, matched related donor allo-HSCT in patients with ALL, debate remains regarding the use of matched related donor allo-HSCT as a postremission therapy in the setting of adult patients with ALL. Based on the poor overall prognosis of this disease, the contention remains that all patients with a suitable matched related donor should undergo allo-HSCT. However, this contention should take into account the significant treatment-related mortality of 20% to 30% associated with allo-HSCT in addition to quality-of-life considerations. Moreover, patients’ age and comorbidities must be carefully considered when determining transplant eligibility to achieve the potential benefit of this modality in terms of overall survival.

Most patients with ALL (>80%), adult and pediatric, will experience disease remission after one or two cycles of induction chemotherapy. Whether patients in first complete remission benefit with matched related donor HSCT versus chemotherapy alone in the adult ALL setting is a critical question with conflicting answers. Adult patients with ALL traditionally have been divided into standard- and high-risk groups based on several clinical and genetic criteria. High-risk patients are variably defined as those older than 35 years, with an elevated white blood cell count at diagnosis, a delayed response (>28 days) after initial induction chemotherapy, and with genetically adverse features, including the presence of the Philadelphia chromosome (Ph ⁺ ), t(1;19), and t(4;11). In high-risk transplant-eligible patients, myeloablative matched related donor allo-HSCT is currently the preferred consolidation treatment in the setting of first complete remission, given several large clinical trials and a meta-analysis showing benefit compared with either chemotherapy alone or autologous HSCT. However, in contrast to these findings, data from the PETHEMA ALL-93 trial and the international collaborative trial conducted by the Medical Research Council (MRC) and the Eastern Cooperative Oncology Group (ECOG), MRC UKALL XII/ECOG E2993, failed to show a similar advantage for patients with high risk disease, again placing the role of matched related donor HSCT for high-risk patients into question.

The high-risk category of patients with ALL harboring Ph+ deserves a separate discussion for several reasons, including (1) poor prognosis predominately secondary to relative chemoinsensitivity, (2) predilection for older patients who may not be able to tolerate intensive therapy, and (3) opportunity for targeted tyrosine kinase inhibitor (TKI) therapy (imatinib, dasatinib, and nilotinib). Before the incorporation of TKIs into treatment regimens, patients with Ph ⁺ ALL fared poorly in the setting of matched related donor HSCT. However, one recently published report of data generated by the MRC UKALL XII/ECOG E2993 showed a significantly improved relapse-free survival in patients with Ph ⁺ ALL after matched unrelated donor or matched related donor HSCT when compared with chemotherapy alone, before the use of a TKI. Although this is the largest prospective study evaluating chemotherapy versus allo-HSCT as postremission consolidation for Ph+ ALL, it has important limitations. Given the age restriction for allo-HSCT on the study (of patients receiving allo-HSCT, 95% were younger than 50 years), the patients who received chemotherapy alone were significantly older than those that received allo-HSCT ( P = .004), which may introduce a potentially large confounder effect, because age was a significant prognostic factor in the multivariate analysis. Additionally, further analysis through intent-to-treat showed nonsignificant differences between the groups, again speaking to the relative chemo-insensitive nature of Ph ⁺ ALL and the intolerance of therapy among advanced-age patients with this disease phenotype.

TKIs in combination with chemotherapy has become an accepted standard of care for inducing remission in patients with Ph ⁺ ALL, showing significant improvements in complete remission rates compared with chemotherapy-only historical controls. The low toxicity of an adjunctive TKI with combination chemotherapy seems to offer access to allo-HSCT for this high-risk and typically advanced-age patient cohort. Considering intent-to-treat models, the efficacy of TKI therapy for patients with Ph ⁺ ALL necessitates reevaluation of the role of allo-HSCT in this disease phenotype. Early results of allo-HSCT in patients with high-risk Ph ⁺ disease treated with a TKI during induction and consolidation before transplantation suggest that adding imatinib before allo-HSCT results in favorable complete remission rates and seems to offer improved disease-free and overall survivals after allo-HSCT transplantation compared with historical controls. More recent studies of a larger Ph ⁺ patient cohorts have confirmed favorable outcomes of TKI in combination with chemotherapy followed by transplantation. In the MRC UKALL XII/ECOG E2993 series, patients randomized to allo-HSCT in the post-TKI era had improved 3-year overall survival compared with patients randomized to allo-HCT pre-TKI based on the same complete remission criteria (56% vs 40%). Lastly, a study from Japan showed added efficacy of TKI in patients experiencing first complete remission before myeloablative allo-HSCT compared with pre-TKI historic controls (3-year overall survival, 65% and 44%, respectively; P = .005).

The more contentious debate has been the role of allo-HSCT in standard-risk adult patients experiencing first complete remission. The largest prospective randomized trial to attempt to answer this question was the MRC UKALL XII/ECOG E2993. In this trial, 1646 patients with Ph-negative ALL underwent a standardized induction, and those that experienced complete remission were biologically randomized to allo-HSCT if a matched related donor was identified and the patient was of appropriate myeloablative versus allo-HSCT age, either younger than 50 (ECOG) or 55 years (MRC), or chemotherapy/autologous HSCT if no matched related donor was identified. The standard-risk matched related donor allo-HSCT arm showed a 5-year overall survival of 62%, which was significantly better than 52% in the no-donor arm ( P = .02). Paradoxically, the high-risk Ph-negative patients did not derive significant advantage from allo-HSCT. In both high- and standard-risk groups, the relapse risk was significantly abrogated in the matched related donor allo-HSCT arm, lending credence to a GvL effect. Thus, this study may pose more questions than it answers, such as whether intensifying consolidation with allo-HSCT truly overcomes the poor prognosis of traditionally defined Ph-negative high-risk patients. Additionally, one could argue that, given the relative success of intensified pediatric-inspired chemotherapy programs, the control chemotherapy group in this large randomized intent-to-treat study may have been suboptimally treated. Lastly, prognostic modeling has improved in the modern era. Thus, strategies to better risk-adapt patients in the hope of potentiating benefit from the toxicity of allo-HSCT consolidation based on clinical response to induction chemotherapy (ie, time to complete remission and minimal residual disease after completion of induction) are being largely adapted in clinical trials in Europe. In addition to identifying the appropriate standard-risk patients in whom to escalate therapy with allo-HSCT, high-risk patients may be afforded the opportunity to be spared allo-HSCT if prompt minimal residual disease-negative status is attained. Thus, despite MRC/ECOG randomized data, the role of allo-HSCT in the contemporary era remains a point of discussion.

Unrelated Allo-HSCT and ALL

Overall, adult patients with ALL experiencing first complete remission seem to benefit from allo-HSCT from a matched related donor; unfortunately, only approximately one-third of these patients have an appropriate matched related donor. Therefore, most patients rely on identification of either an unrelated donor, an umbilical cord blood (UCB) donor, or a haploidentical donor. In all of these settings, one would expect that the risk of transplant-related mortality secondary to GvHD would be increased but with a consequently enhanced GvL effect. However, these presumptions are challenged by published data.

Historically, in the myeloablative setting, patients with a matched unrelated donor have fared poorly compared with those transplanted from a matched related donor secondary to increased transplant-related mortality associated with GvHD. In the contemporary allo-HSCT era of more-resolute human leukocyte antigen (HLA)–matching criteria and improved supportive care, the differences in clinical outcome have become less appreciable between allo-HSCT from a matched related donor and that from a matched unrelated donor. Several studies have addressed this question specifically in the setting of myeloablative allo-HSCT for ALL in first complete remission, showing similar transplant-related mortality, relapse rate, and ultimately overall survival when comparing patients with ALL who underwent either a matched related donor or a matched unrelated donor HSCT. A recent study from Japan showed the traditionally increased risk of transplant-related mortality but concurrently reduced relapse rate in matched unrelated donor HSCT compared with matched related donor HSCT, illustrating the enhanced GvL and GvHD effects, resulting in comparable overall survival. These data support the recommendation that eligible patients in first complete remission, with either a matched related donor or matched unrelated donor available, be considered for an allo-HSCT.

Alternative-Donor Allo-HSCT

Advances in alternative donor transplantation (ie, UCB and haploidentical allo-HSCT) offer another option for patients lacking a suitably matched related or unrelated donor. With increasing numbers of public cord blood banks, UCB in adults is becoming an increasingly viable option, with burgeoning data emerging in only the past 7 years. The early experience showed lower than anticipated degrees of GvHD across greater HLA-barriers compared with traditional volunteer unrelated donor grafts. A significant factor in transplant-related mortality is the total nucleated cell dose infused, with patients receiving less than 2 × 10 ⁷ /kg total nucleated cells exhibiting a higher incidence of graft failure and greater transplant-related mortality compared with those receiving grafts with greater than 2 × 10 ⁷ /kg total nucleated cells. To overcome this limitation, many centers have adopted double-unit UCB transplants. Studies have found that double-unit recipients seem to fare better than single-unit historical controls, despite most patients engrafting with only one of the two infused UCB units. Theories of this benefit include reduced transplant-related mortality related to larger cell dose and brisk myeloid engraftment, and enhanced GvL and subsequent protection from progression of primary hematologic malignancy.

Because the field of UCB transplantation is new, most reports pool acute myeloid leukemia and ALL into a single category of patients with acute leukemia, causing recommendations regarding this modality in the specific setting of ALL to be difficult to make. However, recently reported outcomes of UCB HSCT in a large registry series compared favorably with bone marrow or peripheral blood stem cell allo-HSCT transplants in adult patients with acute leukemia. In this series of more than 1500 patients, leukemia-free survival in patients who received UCB transplant mismatched at zero to two HLA loci was comparable to that of patients who received matched (8/8 HLA-allele matched) or mismatched (7/8 HLA-allele matched) volunteer unrelated donor transplants. Transplant-related mortality was significantly greater for patients who received UCB compared with 8/8 HLA-matched unrelated donors with both peripheral blood stem cell (hazard ratio [HR], 1.62; 95% CI, 1.18–2.23; P = .003) and bone marrow (HR, 1.69; 95% CI, 1.19–2.39; P = .003).

More recent published studies of UCB HSCTs have specifically focused on patients with ALL. In a large retrospective study recently published from Japan, no difference in transplant-related mortality or leukemia-free survival was seen between adult patients with ALL who received an UCB graft mismatched at up to two loci and matched or mismatched bone marrow grafts. Kumar and colleagues compared outcomes of patients with ALL receiving matched related donor HSCT, unrelated matched HSCT, mismatched HSCT, and matched or mismatched UCB transplants. The investigators surprisingly found superior 3-year overall survival rates in the UCB transplant group compared with all other treatment groups, and improved leukemia-free survival, lower relapse rates, and lower treatment-related mortality. The authors reported a statistically significant overall survival in patients with ALL treated with UCB transplant compared with those treated with unrelated donor HSCTs ( P = .01). However, as the authors acknowledge, interpretation of these findings should be tempered by the low numbers of patients analyzed.

A final option for allo-HSCT in patients lacking related, unrelated, or UCB HSCT donors is a haploidentical donor HSCT. In this setting, virtually every patient has a suitable related donor (a parent or sibling). Not surprisingly, early studies using haploidentical HSCTs were hampered by significant incidences of GvHD and graft failure. Over time, modifications in preparative conditioning regimens designed to optimize myeloablation and host immunosuppression, combined with enhanced techniques of T-cell depletion of the graft, and the infusion of markedly high doses of hematopoietic stem cells generated from the donor through mobilization with recombinant human granulocyte colony-stimulating factor, have led to a high rate of engraftment (>95%) with minimal GvHD even in the absence of immune suppression prophylaxis. In a recently published report, patients with high-risk acute leukemias were evaluated after haploidentical HSCT. In patients with high-risk ALL treated with haploidentical HSCTs, Ciceri and colleagues report a leukemia-free 2-year survival rate of 13% for those undergoing transplantation in first complete remission, 30% for those undergoing HSCT in second or further complete remission, and 7% in those undergoing HSCT in nonremission.

Enhanced survival of patients with ALL was recently reported in the setting of unmanipulated, non–T-cell depleted haploidentical HSCTs. Huang and colleagues report more favorable leukemia-free survival in patients with ALL treated with unmanipulated haploidentical grafts, with a 3-year leukemia-free survival of 60% and 25% in those with standard-risk and high-risk disease, respectively. However, these improved survival rates were associated with increased incidences of GvHD. Debate continues regarding the use of haploidentical graft source as opposed to UCB, and vice versa.

Reduced-Intensity Conditioning Allo-HSCT for Adult ALL

Given the typically higher-risk disease in a growing population of older, more-infirm patients with ALL, wherein myeloablative conditioning is prohibitively associated with exceedingly high transplant-related mortality, the need for extending allo-HSCT options with reduced-intensity conditioning has never been greater. This modality sacrifices disease control with reduced intensity of conditioning to minimize transplant-related mortality, thus relying more heavily on GvL. Thus, the gravity of disease control before allo-HSCT carries greater value to outcomes. The feasibility of this approach has been met with somewhat encouraging results given this high-risk patient population. In a recent large retrospective series comparing reduced-intensity conditioning and myeloablative conditioning for Ph-negative ALL, although a trend was seen toward more frequent relapse with reduced-intensity conditioning (35% vs 28% for myeloablative conditioning; P = .08), no difference was seen in overall survival in multivariate analysis ( P = .92). The European Group for Blood and Marrow Transplantation registry data showed decreased nonrelapse mortality with reduced-intensity conditioning compared with myeloablative conditioning (21% vs 29%; P = .03), with an associated increased frequency of relapse (47% vs 31%; P <.001), resulting in a trend toward improved estimated 2-year leukemia-free survival with myeloablative compared with reduced-intensity conditioning ( P = .07). These data illustrate the improved safety of reduced-intensity conditioning at the expense of diminished disease control. Application of reduced-intensity conditioning with UCB transplantation to the older patient population with ALL may be feasible given data from Brunstein and colleagues reporting on predominately double UCB transplants in older patients with hematologic malignancies. Overall, this approach was well tolerated, with modest treatment-related mortality at 3-year follow-up (26%) and promising overall and event-free survival rates (45% and 38%, respectively). A more recent publication from the same institution reported the results of 22 patients with ALL (21 in first complete remission) treated with the same reduced intensity conditioning regimen, followed by 4 of 22 patients receiving a matched related donor HSCT, whereas the remaining 18 patients received UCB donor grafts. Collectively, these older (median age, 49 years) high-risk patients (defined as Ph ⁺ [n = 14], and in second or further complete response [n = 10]) tolerated therapy well, with a treatment-related mortality rate of 27%, disease relapse rate of 36%, and promising overall survival rate at 3 years of 50%. Interpretation of these data must be tempered by the small number of patients reported in this study, and requires further confirmation in larger prospective studies.

Novel Approaches to Lowering Risk of GvHD: T-Cell Depletion

With GvHD as the leading cause of transplant-related mortality in allo-HSCT, several groups have studied T-cell depletion of a conventional donor graft as a means of lowering the frequency of this often-fatal complication. The potential risks associated with this approach include increased risk of relapse with reduced GvL effect, and impaired immune reconstitution leading to increased risk of infectious complications post–allo-HSCT. The group at Memorial Sloan-Kettering Cancer Center (MSKCC) recently reported results of 35 adult patients receiving unrelated donor allo-HSCT with ex vivo T-cell depletion for hematologic malignancies, including 13 patients with ALL in remission (3 in first remission, 7 in second complete remission, and 3 in third or further complete remission). Eighteen donors were HLA disparate at 1 to 3 of 10 loci. Despite a large proportion of patients with high-risk ALL (complete remission >1), only one patient with ALL experienced relapse, and the relapse incidence of the entire cohort was 6%. The incidences of acute grade II through IV and chronic GvHD (9% and 29%, respectively) were much lower than historical controls with a non–T-cell depleted allo-HSCT, especially considering the proportion of mismatched donors in the cohort. Among the 35 patients, 5 deaths occurred.

A British group recently reported on their experience with the use of the anti-CD52 antibody alemtuzumab as an in vivo T-cell depleted allo-HSCT in 48 high-risk Ph-negative patients in first complete remission, with one-third of the patients receiving HLA mismatched grafts. The incidences of acute grade II through IV GvHD and extensive chronic GvHD were 27% and 22%, respectively. The overall survival rate for the entire group was 61% at 5 years. Both of these key studies show favorable disease-specific outcomes compared with conventional, non–T-cell depleted allo-HSCT, with a decreased incidence of GvHD. These encouraging results, however, still need to be validated in a randomized prospective fashion.

Allo-HSCT for Relapsed and Refractory Disease

Unfortunately, most patients with relapsed or refractory disease have a less than 50% chance of responding to salvage chemotherapy, and their prognosis is extremely poor. In patients with relapsed disease who have not previously received an allo-HSCT, have chemosensitive disease, have an appropriate HLA-matched donor, and lack prohibitive comorbidities, an allo-HSCT provides the only chance for long-term disease-free survival. For a multitude of reasons, the ability to match these conditions diminishes steeply in the relapsed and refractory setting. In a subset analysis from the MRC UKALL XII/ECOG E2993 study, patients with relapsed disease receiving an allo-HSCT from related or unrelated donors had improved overall survival at 5 years (23% and 16%, respectively) compared with those that did not proceed to allo-HSCT (4% overall survival at 5 years). Despite the high potential of obvious confounders in this carefully selected subset of patients, the accepted standard is to proceed to allo-HSCT in chemosensitive relapsed and refractory ALL in those who are eligible, considering the incurability with chemotherapy alone.

Donor Lymphocyte Infusion

Donor lymphocyte infusion has been shown to elicit a good response, mediated through a GvL effect, in patients with chronic myelogenous leukemia (CML) who experience relapse after allo-HSCT. However, this technique is rarely successful in relapsed ALL, with a reported long-term disease-free survival ranging from 0% to 13%.

The reasons for the suboptimal response with donor lymphocyte infusion in ALL likely stem from several factors: a lack of adequate T-cell–mediated GvL, the delayed effects of donor lymphocyte infusion in patients with aggressive disease, or a lack of costimulatory molecule on the tumor. Porter and colleagues addressed the latter issue through treating seven patients with relapsed ALL post–allo-HSCT with donor lymphocytes that have been activated and costimulated ex vivo using CD3/CD28 agonist antibodies. In this phase I trial, four of the patients experienced a complete remission, but three of four patients experienced relapse, with only one patient alive in complete remission at more than 11 months, showing the limitation of the conventional donor lymphocyte infusion in relapsed ALL.

A modified approach to donor lymphocyte infusion is the enrichment of donor T cells targeted to antigens overexpressed on tumor cells. Wilms tumor 1 antigen (WT-1) is one antigen that is overexpressed on both acute myelogenous leukemia and ALL tumor cells. WT-1 is immunogenic and may represent an attractive target for adoptive T-cell therapy, as suggested by a recent study by Rezvani and colleagues, who reported WT-1 specific CD8 ⁺ T-cell responses after allo-HSCT in five of seven patients, and a subsequent molecular disease relapse (ie, recurrent WT-1 transcript detection) associated with loss of detectable WT-1–specific CD8 ⁺ T cells. Similarly, investigators at MSKCC and the Fred Hutchinson Cancer Research Center (FHCRC) have developed a way to enrich for WT-1–specific donor T-cell populations through co-culture of donor T cells on antigen-presenting cells pulsed with WT-1 peptides. Currently, both MSKCC (NCT00620633) and the FHCRC (NCT00052520) have open phase I clinical trials treating relapsed acute leukemias and myelodysplastic syndromes after allo-HSCT with WT-1–specific donor T cells. The completion of these trials will provide more information on the efficacy of tumor-specific alloreactive T cells in ALL.

Genetically Modified Tumor-Targeted T Cells

Given the limited GvL effect shown with donor T cells in ALL, several investigators have studied a novel form of adoptive cellular therapy through genetically modifying autologous T cells to target specific tumor antigens. One way of genetically modifying T cells is through gene transfer of the α and β chain subunits of the T-cell receptors derived from T-cell clones specific to tumor antigens. This approach has been shown to be feasible in clinical trials of metastatic melanoma, but published data using this approach in hematologic malignancies are limited. Moreover, because the T-cell receptor gene transfer approach can only recognize tumor antigens that are processed and presented by HLA molecules, specificity of the T-cell receptor is restricted to specific patient HLA phenotypes and therefore lacks universal applicability. In addition, many tumor cells downregulate HLA molecules or have dysfunctional antigen-presenting machinery, so that the targeted tumor-derived peptides are often not adequately presented on the tumor cell surface.

One way to circumvent these limitations of T-cell receptor gene transfer is the use of chimeric antigen receptors (CARs). CARs are composed of a single-chain variable-fragment (scFv) antibody specific to tumor antigen, fused to a transmembrane domain and a T-cell signaling moiety, most commonly either the CD3-ζ or Fc receptor γ cytoplasmic signaling domains. The resulting receptor, when expressed on the surface of the T cell, mediates binding to the target tumor antigen through the scFv domain, which subsequently mediates an activating signal to the T cell, inducing target cell lysis.

The use of T cells engineered to express CARs has several advantages over conventional allo-HSCT. First, because this approach uses autologous patient-derived T cells, no risk of GvHD exists. Second, tumor-specific T cells may be rapidly generated ex vivo in the laboratory. Third, because CAR recognition of target tumor antigen is HLA-independent, CAR-modified T cells can be applied to all HLA types and are less likely to generate resistant tumor cells through downregulation of HLA molecules. And lastly, CARs can be further modified to insert additional genes to express T-cell costimulatory molecules or proinflammatory cytokines to enhance antitumor efficacy.

Genetically Modified T Cells in ALL

Although data are limited regarding the use of T-cell receptor gene transfer for genetic targeting of T cells in ALL, several groups, including the authors’, have investigated the use of CARs as a method of adoptive cellular therapy for ALL.

The first requirement to redirect CAR-modified T cells toward a selected tumor cell is identification of an appropriate target molecule that is selectively expressed on cancer cells. With regard to ALL of B-cell origin, CD19 is an ideal target for several reasons: (1) in contrast to CD20, which is the target of current antibody-based immunotherapy, CD19 is expressed on the earliest B-precursor lymphocytes; (2) CD19 expression is retained during the process of neoplastic transformation; and (3) CD19 is absent on pluripotent hematopoietic stem cells. Furthermore, a recent report showing the efficacy of bispecific single-chain antibody targeting the CD19 antigen (blinatumomab) suggests that CD19 is an attractive target for cellular immunotherapy in ALL.

In fact, human T cells retrovirally modified to express CD19-targeted CAR have been shown to effectively lyse CD19 ⁺ tumor cells in vitro and eradicate systemic CD19 ⁺ tumors in SCID Beige mice. Further studies in the authors’ laboratory have shown in vivo that efficacy and persistence of these modified T cells is enhanced through costimulation. Because most B-cell tumors fail to express costimulatory ligands (CD80 and CD86) required to generate optimal activation and proliferation of T cells, the authors and others have further modified the CAR to include the signaling domain of the T-cell costimulatory receptors (eg, CD28, 4-1BB, OX40). The resulting second-generation CARs exhibit in vitro activation and proliferation in the absence of exogenous costimulatory ligands, and enhanced in vivo antitumor efficacy in immunodeficient mice bearing systemic human pre–B-cell ALL tumors lacking costimulatory CD80 and CD86 ligands. More recently, several investigators constructed and tested third-generation CARs containing tandem cytoplasmic signaling domains from two costimulatory receptors (ie, CD28-4-1BB or CD28-OX40) showing potentially enhanced T-cell signaling capacity when compared with second-generation CARs, but these have yet to be studied in the clinical setting.

Clinical Trials with CD19-Targeted Modified T Cells in ALL

These promising preclinical data have led to a robust translation of CD19-targeted CAR ⁺ T cells to the clinical setting for various B-cell hematologic malignancies. Currently, 11 active and 3 soon-to-open phase I clinical trials are targeting CD19 ( Table 1 ). Although many of these trials have recently opened, several published preliminary results suggest that adoptive cellular therapy using autologous CD19-targeted CAR ⁺ T cells is a promising treatment approach for B-cell malignancies. For example, investigators at the National Cancer Institute reported a dramatic regression of lymphadenopathy lasting 32 weeks in a patient with advanced follicular lymphoma who was treated with a preparative chemotherapy (60 mg/kg of cyclophosphamide for 2 days and 25 mg/m ² of fludarabine for 5 days) followed by autologous CD19-targeted CAR ⁺ T cells and interleukin (IL)-2. The authors also have observed a dramatic reduction of lymphadenopathy that lasted for 9 months in one patient and stable disease in two patients with chemotherapy-refractory relapsed chronic lymphocytic leukemia who were treated with 1.5 g/m ² of cyclophosphamide conditioning one day before infusion of autologous CD19-targeted CAR ⁺ T cells. Investigators from the University of Pennsylvania recently reported complete responses in three patients with advanced stages of indolent B-cell lymphomas and chronic lymphocytic leukemia, all treated with autologous CD19-targeted CAR ⁺ T cells.

Table 1

Summary of open and planned clinical trials with CD19-targeted chimeric T cells

Cell Source	Patient Population	Trial Design	Accompanying Lymphodepleting Cytotoxic Therapy	Trial Status	Trial Site
Autologous T cells	Relapsed or refractory CLL	Phase I dose-escalation trial	Cy	Open	United States, New York
Autologous T cells	Relapsed or refractory, or MRD + ALL	Phase I dose-escalation trial	Cy	Open	United States, New York
Autologous T cells	MRD + or residual disease after frontline CLL therapy	Phase I dose-escalation trial; consolidation therapy after up-front chemotherapy	Cy	Open	United States, New York
Autologous T cells	Relapsed or refractory low- to intermediate-grade NHL and CLL	Phase I dose-escalation trial	None	Open	United States, Texas
Autologous T cells	Relapsed or refractory B-cell leukemia/lymphoma (ALL, CLL, FL, MCL, DLBCL)	Phase I dose-escalation trial	None	Open	United States, Pennsylvania
Autologous T cells	Relapsed or refractory FL	Phase I	Fludarabine + rituximab	Open	United States, California
Autologous T cells	CD19-expressing B-cell malignancy of any type	Phase I	Fludarabine + Cy	Open	United States, National Institutes of Health
Autologous T cells	Relapsed or refractory low- to intermediate-grade NHL and CLL	Phase I; modified T-cell infusion after autologous HSCT	Autologous HSCT regimen (carmustine, etoposide, cytarabine, melphalan, rituximab)	Open	United States, Texas
Donor-derived EBV-specific T cells	MRD + or relapsed ALL after allo-HSCT	Phase I dose-escalation trial	Cy	Open	United States, New York
Donor-derived multivirus-specific T cells	Relapsed B-ALL after allo-HSCT	Phase I dose-escalation trial	None	Open	United States, Texas
Donor-derived T cells	Relapsed B-cell leukemia/lymphoma after allo-HSCT	Phase I dose-escalation trial	N/A	Open	United States, NIH
UCB-derived T cells	Relapsed or refractory ALL, NHL, SLL, CLL	N/A	N/A	Pending	United States, Texas
Autologous T cells	High-risk, intermediate-grade NHL	Phase I/II trial; modified T-cell infusion after auto-HSCT	N/A	Pending	United States, California
Donor-derived EBV-specific T cells	High-risk or relapsed B-ALL after allo-HSCT	Phase I	N/A	Pending	Europe (France, Germany, Italy, United Kingdom)

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